High‐Valent Copper Catalysis Enables Regioselective Fluoroarylation of Gem‐Difluorinated Cyclopropanes

Abstract Transition‐metal (TM) catalyzed reaction of gem‐difluorinated cyclopropanes (gem‐DFCPs) has drawn much attention recently. The reaction generally occurs via the activation of the distal C─C bond in gem‐DFCPs by a low‐valent TM through oxidative addition, eventually producing mono‐fluoro olefins as the coupling products. However, achieving regioselective activation of the proximal C─C bond in gem‐DFCPs that overcomes the intrinsic reactivity via TM catalysis remains elusive. Here, a new reaction mode of gem‐DFCPs enabled by high‐valent copper catalysis, which allows exclusive activation of the congested proximal C─C bond is presented. The reaction that achieves fluoroarylation of gem‐DFCPs uses NFSI (N‐fluorobenzenesulfonimide) as electrophilic fluoro reagent and arenes as the C─H nucleophiles, enabling the synthesis of diverse CF3‐containing scaffolds. It is proposed that a high‐valent copper species plays an important role in the regioselective activation of the proximal C─C bond possibly via a σ‐bond metathesis.


Introduction
Fluorine substitution is very important in modulating the properties of organic molecules by introducing fluorine atoms and/or fluorinated groups. [1]1a] Consequently, the development of a new strategy that can efficiently incorporate fluorine motifs into organic molecules is therefore in high demand. [2]In DOI: 10.1002/advs.202401243 this context, gem-difluorinated cyclopropanes (gem-DFCPs), owing to their facile availability (for selected reviews and reports on the synthesis of gem-DFCPs, see ref. [3]) and unique reactivity [4] (Scheme 1a, left), have emerged as highly versatile building blocks for the synthesis of fluorine-containing molecules.In recent years, the utilization of transition-metal (TM) catalysts renders the cross-coupling reactions of gem-DFCPs with various nucleophiles (for reviews, see ref. [5]; for selected reports on Pd catalysis with linearselectivity, see ref. [6]; for selected reports on Pd catalysis with branched-selectivity, see ref. [7]; for Rh catalysis, see ref. [8]; for Co catalysis, see ref. [9]; for Ni catalysis, see ref. [10]), providing a highly efficient approach for the synthesis of monofluorinated alkenes (instead of monofluorinated alkenes, gem-difluorinated carbocycles and fully-substituted alkyl vinyl ethers can also be synthesized from gem-DFCPs by Rh-or Cu-catalysis, see ref. [11]).[8] To the best of our knowledge, strategy that can activate the congested proximal C─C bond in gem-DFCPs under TM catalysis has not been developed yet (for representative reports on TM-free reaction of gem-DFCPs, see ref. [12]) Compared with the activation mode of C─C cleavage via oxidative addition with low-valent TM (for reviews on C─C activation via oxidative addition with low-valent TM, see ref. [13]), it can be envisaged that a high-valent TM complex (for selected reviews, see ref. [14]) may be able to activate the C─C bond in gem-DFCPs considering its partial -bond nature in cyclopropyl ring.In the hypothesis, the high-valent TM complex A, generated via oxidative addition with an electrophilic reagent, is highly electrophilic and possible to interact with the C─C bond in gem-DFCPs, for example, through a -bond metathesis (B) to give a benzyl metal species C. The reaction of C with a suitable nucleophile via reductive elimination or another process would deliver the C─C difunctionalization product (Scheme 1b).
Based on this concept, we herein disclosed that a highvalent copper-catalyzed (for selected reports on high-valent Cu catalysis, see ref. [15]) regioselective fluoroarylation of gem-DFCPs through proximal C─C bond activation by utilizing NFSI  b) The ratio (p:o = 2a:2a′) was measured by 19 F NMR; c) Total yields of 2a and 2a′ were determined by 1 H NMR using 1,1,2,2-tetrachloroethane as the internal standard; d) Isolated yield of the major product 2a.
(N-fluorobenzenesulfonimide) as the oxidant and electrophilic fluorine source and simple electron-rich arenes as the C─H nucleophiles.In this new reaction mode of gem-DFCPs, it was proposed that the regioselective proximal C─C activation is triggered by the high-valent copper species, other than by lowvalent metal via previously well-developed oxidative addition process (Scheme 1c).Significantly, this transformation allows for the synthesis of exclusive CF 3 -containing scaffolds via regioselective fluoroarylation, rather than fluoroallyl compounds via fluoroallyl chemistry, by sequentially introducing a fluorine group and an aryl nucleophile regioselectively.Note that NFSI has been extensively utilized in copper-catalyzed reactions of simple cyclopropanes. [16]In these reactions, the Cu III species undergoes an LMCT process to generate a nitrogen radical, which triggers the ring-opening process with the nitrogen fragment of NFSI incorporated in the final product (Scheme 1d).

Results and Discussion
Our investigation began by employing 1-(2,2difluorocyclopropyl)−4-methylbenzene (1a) as the model substrate, anisole as the C─H nucleophile, and NFSI as the electrophilic fluorine reagent to optimize the reaction conditions (Table 1).After systematically optimization, it was found that the designed reaction proceeded smoothly by using 10 mol% Cu(MeCN) 4 PF 6 , 10 mol% [B(neop)] 2 [bis(neopentyl glycolato)diboron], [17] and PhCl (1 m) as the solvent without additional ligand at 80 °C for 3 h.Under the optimized conditions, the reaction produced the fluoroarylation products with a para/ortho selectivity of 11:1, and the major product 2a was isolated in a 73% yield (entry 1).The control experiment showed that the reaction didn't work without the participation of Cu(MeCN) 4 PF 6 (entry 2).In the absence of [B(neop)] 2 , there is a substantial decline in the conversion of gem-DFCP 1a, resulting in a low  (entries 19-20).Higher reaction temperature compromised the regioselectivity, whereas lower reaction temperature decreased the reaction efficiency (entries 21-22).
With the optimized conditions in hand, we proceeded to explore the scope of the Cu-catalyzed fluoroarylation reaction.We initially investigated the reaction scope of gem-DFCPs in combination with anisole as the nucleophilic coupling partner (Scheme 2).Aryl gem-DFCPs bearing electron-donating groups (2a-2d) and a phenyl group (2e) exhibited favorable reactivity, leading to the formation of fluoroarylation products with good yields and para-selectivity.Simple phenyl (2f) and electron-deficient aryl groups (2g-2i) in gem-DFCPs were tolerated under the optimized reaction conditions, giving the corresponding products in moderate yields with para-selectivity of 4:1.Aryl gem-DFCPs with strong electron-deficient aryl groups (CF 3 , CO 2 Et) failed to form the desired products.The substrates with ortho-(2j) or meta-substituted aryl moieties (2k) displayed satisfactory reactivity, providing the desired products with 63% and 57% yields, respectively.Di-substituted aryl (2l) and naphthyl (2m, 2n) substituted gem-DFCPs work smoothly in this transformation.Note that gem-DFCPs containing oxygen (2o) or sulfur (2p) heterocycle were also competent substrates in this reaction.An intriguing substrate is 4-cyclopropyl aryl gem-DFCP, which contains two cyclopropyl rings; it was found that only the gem-difluorinated cyclopropane expressed the fluoroarylation reactivity under the Cu-catalyzed conditions, leaving the simple cyclopropyl ring untouched (2q).When 9-anthracenyl gem-DFCP (1r) was used as the substrate, an abnormal fluoro arylation product was formed in decent yield, in which the arylation occurs at the para-position of the anthracyl moiety (2r).It was found that gem-DFCP derived from indene provided the target product in a total yield of 73% with para/ortho selectivity of 2.6:1 and trans/cis selectivity of 6:1 under the optimized reaction conditions (2s).It is noteworthy that 1,1-disubstituted gem-DFCPs show satisfied reactivity toward fluoroarylation, resulting in the formation of CF 3containing scaffolds with an all-carbon quaternary center (2t-2v).Similarly, the use of 1,3-disubstituted gem-DFCP provides the product with a substituent at the -position of the CF 3 moiety (2w).Finally, the participation of styryl-substituted gem-DFCP in the reaction gives a pair of products in 64% total yields with a ratio of 1.8:1 (2x, 2x′), in which a migration of the double bond occurs in the minor product.
Subsequently, we evaluated the reactivity of various arenes in our reaction (Scheme 3).Substrates with bulkier alkoxyl (4a) and phenoxyl (4b) groups exhibit good regioselectivity and decent yields in the fluoroarylation reaction.The reaction of 2-halogen-substituted anisoles proceed smoothly, delivering the corresponding products (4c-4e) with exclusive para-selectivity.Likewise, anisole derivatives substituted with ester (4f) or methyl group (4g) at the ortho-position yield the desired products in moderate yields with no other regio isomers observed.When meta-substituted anisole derivatives were used as the substrates, the regio-selectivity was decreased to some extent (4h, 4i) with moderate to good yields.Note that the aryl C─H functionalization Scheme 4. Synthetic applications.
occurs at the ortho-position of the methoxyl group (4j, 4k) when the para-position of the substrates was blocked.In addition, naphthalene derivatives (4l, 4m) are competent nucleophiles in this transformation; while simple naphthalene provides the products with poor regioselectivity, excellent regioselectivity was observed in the reaction of fluoronaphthalene.Finally, we discovered that benzothiophene derivatives could serve as the nucleophiles to participate in the fluoroarylation reaction, in which the C─H functionalization mainly occurs at 3-position (4n) or 2-position (4o) if the 3-position is substituted; however, more electron-rich hetereoarenes (indole derivatives) were unsuccessful nucleophiles in this transformation, presumably due to their incompatibility with oxidative conditions.
The utility of our reaction was further demonstrated through a gram-scale synthesis and various synthetic applications (Scheme 4).First, we conducted the model reaction on a gramscale, which provides a 74% yield (1.31 g) of the desired product 2a with good regioselectivity (p:o = 10:1) (Scheme 4a).Second, the resulting CF 3 products can be smoothly converted into the corresponding CF 2 -containing molecules.For example, treatment 2a with potassium tert-butoxide gives the HF eliminated intermediate 5a, which then undergoes hydrogenation to deliver the difluoromethyl product 6a in 98% yield.The two-step sequence together with our model reaction provides an alternative method to access , -diaryl difluoromethyl scaffolds (6a-6d) (Scheme 4b).Furthermore, the electron-rich aryl moiety in the products (2a, 2v) can undergo chemoselective oxidative degradation in the presence of RuCl 3 /NaIO 4 , resulting in the formation of the corresponding carboxylic acids (7a, 7v) with yields of 60% and 92%, respectively (Scheme 4c). [18]These two types of downstream transformations realized formal hydroarylation and fluorocarboxylation of gem-DFCPs, respectively, which significantly enriched the synthetic applications of gem-DFCPs.
To better understand the reaction mechanism of the coppercatalyzed fluoroarylation transformation, a set of control experiments was then carried out.First, compound 8 was used instead of anisole under the copper-catalyzed conditions, but failed to produce the allylation product.Such a control experiment indicates that a benzyl radical, which was proposed in visible-light-promoted radical-type fluoroallylation reaction of electron-rich aryl substituted gem-DFCPs, [12c] was not involved in this Cu-catalyzed reaction (Scheme 5a).Second, during the in-vestigation of the reaction scope of gem-DFCPs, it was found that our catalytic system has privileged reactivity on gem-DFCP over simple cyclopropane (1q to 2q).It is indeed that simple arylcyclopropane 9 hardly shows reactivity under the standard reaction conditions, and only a trace amount of fluoroarylation product 10 was obtained with 9 being recovered over 80% (Scheme 5b).Next, we investigated the fate of the model reaction by removing the arene nucleophile, and we detected the formation of eliminated trifluoromethyl product 11a and fluoroamination product 11b in 10% and 27% yields, respectively.This result indicates the possible involvement of a high-valent benzyl-copper species or a benzyl carbocation intermediate in the reaction, Scheme 6. Proposed mechanism.
which undergoes elimination, C─N reductive elimination, or Friedel-Crafts-type alkylation to give 11a, 11b, and 2a, respectively.Treatment of these two byproducts 11a and 11b under the standard reaction conditions failed to produce the original fluoroarylation product (Scheme 5c).Finally, enantiopure gem-DFCP 1e was used as the substrate to probe the stereochemistry of the arylation process under the standard reactions, and it was found only racemic fluoroarylation product 2e was obtained.Besides, the corresponding aminoarylation product 12 was also racemic when the reaction was carried out in the absence of anisole.This observation further supports the involvement of the carbocation intermediate in the arylation step (Scheme 5d).
Based on these experimental observations and previous studies, [16] we proposed a simplified mechanism for this reaction (Scheme 6).Initially, Cu(I) is oxidized by NFSI to produce F─Cu(III)─N(PhSO 2 ) 2 species A, which is highly electrophilic and may activate the proximal C─C bond in gem-DFCP possibly via a -bond metathesis to form a benzyl─Cu(III) species B. Finally, complex B is equilibrated with the Cu(I) and benzyl cation species C, [19] which is then captured by an electron-rich arene via Friedel-Crafts process to produce the fluoroarylation product.Meanwhile, it is also possible that the F─Cu(III)─N(PhSO 2 ) 2 species A undergoes comproportionation with the Cu(I) or releases a nitrogen radical to form a Cu(II)─F species D, which then triggers the C─C bond activation.Nevertheless, in addition to the proposed -bond metathesis, we cannot rule out the possibility of a stepwise mechanism involving SET process to cleave the C─C bond (see Supporting Information for more details), and further inverstigations are required to better understand the details of the reaction mechanism.

Conclusion
In conclusion, we have developed a high-valent copper-catalyzed regioselective fluoroarylation of gem-DFCPs with electron-rich arenes as the C─H nucleophiles and NFSI as the electrophilic fluoro reagent.It is proposed that the regioselective congested proximal C─C bond activation proceeds via a concerted -bond metathesis with a high-valent Cu─F species accompanying the C─F bond formation, and the arylation occurs through a Friedel-Crafts process with the benzyl carbocation intermediate that is generated from the high-valent benzyl-copper species.The reaction expresses a broad substrate scope with respect to both gem-DFCPs and simple arenes, enabling the synthesis of trifluoromethylated products to a great diversity.Furthermore, the successful gram-scale synthesis and downstream transformations further validate the applicability of this methodology for accessing organofluorine molecules from gem-DFCPs.This new reaction model not only broadens the synthetic applications of gem-DFCPs in organic synthesis, but also provides new opportunities for exploring high-valent TM in C─C bond activation.

Table 1 .
Optimization of reaction conditions.